Hydrogen sulfide, a lethal gas best known for smelling like rotten eggs, turns out to play key roles in the body – a finding that could lead to new treatment for heart attack victims and others (Scientific American, 302: 66-71, 2010). Research over the last decade has revealed critical biomedical implications of hydrogen sulfide (H2S), a gasotransmitter produced in almost every type of cells with cysteine and homocysteine as substrates. Cystathionine gamma lyase (CSE) plays the most important role in cardiovascular system for the endogenous production of H2S. It is localized in the cytosol of vascular smooth muscle cells (SMCs) under resting conditions. H2S produced in the cytosol of SMCs stimulates KATP channels, leading to vascular relaxation. CSE can be transported into mitochondrion upon the sustained elevation of intracellular calcium level to produces H2S inside mitochondria. The mitochondria-produced H2S decreases ATP production under nomoxia condition but increases it under hypoxia condition. This oxygen-sensitive mitochondrial production of H2S may be important for regulation of vascular remodeling and proliferation. On the other hand, H2S is produced in vascular endothelial cells (ECs) via a calcium/calmodulin-dependent mechanism. Deficiency in endothelium production of H2S leads to delayed wound healing, suppressed endothelial proliferation and migration, vulnerability of endothelium to hyperglycemia damage, abolished endothelium-dependent vasorelaxation, and age-dependent development of hypertension. Micro-electrode recording of the membrane potential changes in endothelium-intact peripheral vascular tissues has provided direct evidence that H2S is an endothelium-derived hyperpolarizing factor (EDHF). As an EDHF, H2S induces greater hyperpolarization of SMCs from female mouse mesenteric arteries than that from male ones. In conclusion, the production of hydrogen sulfide in cardiovascular system is mediated by different mechanisms in different types of cells. By regulating mitochondrial functions and by acting on KATP channels in vascular SMCs and small to medium conductance KCa channels in ECs (as an EDHF), H2S differentially modulates the proliferation of SMCs and ECs and induces vasorelaxation.